The goal of this application is to produce pilot-scale libraries derived from an array of novel heterocyclic scaffolds. We aim to produce "drug-like" and "natural product-like" libraries for HTS in order to maximize the probability of procuring compounds that have a high likelihood of interacting with biomolecular targets. Ultimately, these libraries will be evaluated via the Molecular Library Screening Network (MLSCN) in order to uncover lead structures for further development. We are well positioned to meet this goal by employing methodologies developed in our laboratories that focus on scaffolds that are designed according to medicinal chemistry principles, and use efficient scaffold generation/diversification strategies and facilitated synthetic protocols for library production. In many cases, the proposed libraries have been identified as part of target-based discovery programs within individual research efforts at the University of Kansas (KU). These efforts are augmented by expertise in a number of Centers of Excellence at the University of Kansas, including centers in: (i) Combinatorial Methodologies and Library Development, (ii) Cancer Experimental Therapeutics, (iii) Protein Structure and Function, and (iv) a state-of-the-art High-Throughput Screening Laboratory. This combination of infrastructure and expertise enables us to produce scalable, diverse libraries based on a wide variety of novel scaffolds and allows us to probe biological and chemical space in a dynamic manner. To accomplish this, libraries containing 60-100 compounds in sufficient quantities (10-15 mgs) for HTS on numerous platforms within the MLSCN will be made. Specific efforts proposed herein include library validation by computational methods including diversity-space mapping, the use of facilitated synthetic protocols based on high-load ROMP-reagents and other supported reagents, and both solution-phase and Irori-based solid phase synthetic protocols. A number of libraries are proposed displaying a diverse array of scaffolds, including: (i) turn-inspired peptidomimetics, (ii) sulfur- and phosphorus-containing heterocycles, and (iii) heterocyclic natural product-like scaffolds. [unreadable] [unreadable]